Anxiety and affective disorders constitute a group of heterogeneous illnesses that are common and show significant heritability. Considerable work has focused on identifying the genes involved in anxiety and affective disorders providing interesting leads, but no definitive answers. One of the most prominent childhood risk factors for the development of these illnesses is behavioral inhibition (BI), a temperamental disposition characterized by extreme shyness and inhibition in response to novel situations or strangers. Using young rhesus monkeys, we have developed a model that is analogous to childhood BI and have demonstrated that individual differences in monkey BI are significantly heritable. In addition, we have used functional imaging to identify the brain regions associated with BI. In this project we will measure BI, associated physiological parameters, and functional brain activity in a large multi-generation pedigree of rhesus monkeys. These phenotypes will be used in whole genome linkage analyses to investigate the genetic basis of brain mechanisms underlying anxiety and depression. By combining proven approaches to the study of the genetics of complex disease with simultaneous analysis of intermediate brain reactivity phenotypes, our novel strategy using young rhesus monkeys will: 1) identify novel genes that influence BI, 2) quantitate the influence of genetic variation on individual differences in reactivity of the neurocircuitry underlying emotion, and 3) determine specific genes that are involved in mediating both individual differences in BI and increased reactivity of emotion-related brain circuits. These studies are not feasible in rodent species or humans. The proposed experiments provide an invaluable opportunity to identify novel genetic factors that play a major role in the development of human anxiety and affective disorders, results that will be immediately relevant to children at risk for the development of psychopathology. PUBLIC HEALTH RELEVANCE Anxiety and affective disorders constitute a group of mental illnesses that can be inherited. Using young rhesus monkeys as subjects, this study will: 1) identify genes that influence behavioral inhibition, 2) quantitate the influence of genetic variation on individual differences in reactivity of emotion-related brain circuits, and 3) determine specific genes that are involved in mediating both individual differences in behavioral inhibition and increased reactivity of emotion-related brain circuits. The proposed experiments provide an invaluable opportunity to identify genetic factors that play a major role in the development of human anxiety and affective disorders, results that will be immediately relevant to children at risk for the development of psychopathology. [unreadable] [unreadable] [unreadable]